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US 2011/0033457 A1Published application
Combination of epothilone analogs and chemotherapeutic agents for the treatment of proliferative diseases
AssigneeBristol-Myers Squibb Company
InventorFRANCIS Y.F. LEE
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Abstract
Compositions and methods are disclosed which are useful of the treatment and prevention of proliferative disorders.
Claims68
A method for the treatment of proliferative diseases, including cancer, which comprises administering to a mammalian specie in need thereof a synergistically, therapeutically effective amount of (1) at least one anti-proliferative agent(s) and 2) a compound of formula I,
- wherein:
- Q is selected from the group consisting of
- G is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo,
- W is O or N R15;
- X is O or H, H;
- Y is selected from the group consisting of O;
- H, OR16;
- OR17, OR17;
- NOR18;
- H, NHOR19;
- H, NR20R21;
- H, H;
- and CHR22;
- wherein OR17, OR17 can be a cyclic ketal;
- Z1 and Z2 are independently selected from the group consisting of CH2, O, NR23, S, and SO2, wherein only one of Z1 and Z2 can be a heteroatom;
- B1 and B2 are independently selected from the group consisting of OR24, OCOR25, and O—C(═O)—NR26R27, and when B1 is H and Y is OH, H, they can form a six-membered ring ketal or acetal;
- D is selected from the group consisting of NR28R29, NR30COR31 and saturated heterocycle;
- R1, R2, R3, R4, R5, R6, R7, R13, R14, R18, R19, R20, R21, R22, R26 and R27 are independently selected from the group consisting of H, alkyl, substituted alkyl, and aryl, and when R1 and R2 are alkyl can be joined to form a cycloalkyl, and when R3 and R4 are alkyl can be joined to form a cycloalkyl;
- R9, R10, R16, R17, R24, R25 and R31 are independently selected from the group consisting of H, alkyl, and substituted alkyl;
- R8, R11, R12, R28, R30, R32, and R33 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl and heterocyclo;
- R15, R23 and R29 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo, R32C═O, R33SO2, hydroxy, O-alkyl or O-substituted alkyl;
- and
- pharmaceutically acceptable salts thereof and any hydrates, solvates or geometric, optical and steroisomers thereof;
- with the proviso that compounds wherein
- W and X are both O;
- and
- R1, R2 and R7 are H;
- and
- R3, R4 and R6 are methyl;
- and
- R8 is H or methyl;
- and
- Z1 and Z2 are CH2;
- and
- G is 1-methyl-2-(substituted-4-thiazolyl)ethenyl;
- and
- Q is as defined above
- are excluded;
- provided that the antiproliferative agent is administered in combination with the Formula I compound.
36 more elements
A method for the treatment of proliferative diseases, including cancer, which comprises administering to a mammalian specie in need thereof a synergistically, therapeutically effective amount of (1) at least one anti-proliferative agent(s) and (2) a compound of Formula II
- P-Q is a C, C double bond or an epoxide;
- G is
- R is selected from the group of H, alkyl, and substituted alkyl;
- R1 is selected from the group consisting of
- R2 is
- G1 is selected from the group of H, halogen, CN, alkyl and substituted alkyl;
- G2 is selected from the group of H, alkyl, and substituted alkyl;
- G3 is selected from the group of O, S, and NZ1;
- G4 is selected from the group of H, alkyl, substituted alkyl, OZ2, NZ2Z3, Z2C═O, Z4SO2, and optionally substituted glycosyl;
- G5 is selected from the group of halogen, N3, NCS, SH, CN, NC, N(Z1)3+ and heteroaryl;
- G6 is selected from the group of H, alkyl, substituted alkyl, CF3, OZ5, SZ5, and NZ5Z6;
- G7 is CZ7 or N;
- G8 is selected from the group of H, halogen, alkyl, substituted alkyl, OZ10, SZ10, NZ10Z11;
- G9 is selected from the group of O, S, —NH—NH— and —N═N—;
- G10 is N or CZ12;
- G11 is selected from the group of H2N, substituted H2N, alkyl, substituted alkyl, aryl, and substituted aryl;
- Z1, Z6, Z9, and Z11 are independently selected from the group H, alkyl, substituted alkyl, acyl, and substituted acyl;
- Z2 is selected from the group of H, alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;
- Z3, Z5, Z8, and Z10 are independently selected from the group H, alkyl, substituted alkyl, acyl, substituted acyl, aryl, and substituted aryl;
- Z4 is selected from the group of alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;
- Z7 is selected from the group of H, halogen, alkyl, substituted alkyl, aryl, substituted aryl, OZ8, SZ8, and NZ8Z9;
- and
- Z12 is selected from the group of H, halogen, alkyl, substituted alkyl, aryl, and substituted aryl;
- with the proviso that when R1 is
- G1, G2, G3 and G4 cannot simultaneously have the following meanings:
- G1 and G2=H, G3=0 and G4=H or Z2C═O where Z2=alkyl group.
23 more elements
Dependencies are inferred from the claim text.